Clinicopathological Features and Risk Stratification of Multiple-Classifier Endometrial Cancers: A Multicenter Study from Poland

Rationale: The ProMisE molecular classification improves risk assessment in endome-trial cancer (EC), but 3–11% of cases exhibit overlapping molecular features, compli-cating clinical decisions. We analyzed the prevalence and clinicopathological profiles of multiple-classifier ECs in a large Polish cohort. Methods: In this retrospective study (2022–2025), 1075 ECs from four institutions were classified by MMR and p53 immunohistochemistry and POLE exon sequencing. Tumors showing ≥2 molecular features (e.g., MMRd–p53abn, POLEmut–p53abn) were categorized as multiple-classifier ECs. Results: Multiple-classifier ECs comprised 6.9% (74/1075), with MMRd–p53abn (3.9%) being most common. These tumors exhibited more aggressive features vs MMRd-only: G3 (28.57% vs 11.79%, p=0.002), non-endometrioid histology (11.9% vs 2.85%, p=0.018), and higher-risk stratification (59.52% vs 37.80%, p=0.001). POLEmut–p53abn (N=4) and POLEmut–MMRd–p53abn (N=10) tumors showed advanced stages (75% and 40% FIGO III–IV, respectively), in contrast to classical POLEmut tumors (6.7% FIGO III–IV), and higher rates of nodal metastases. Conclusion: Co-occurrence of molecular classifiers, including triple-classifier tumors, correlates with more adverse profiles and may undermine current stratification para-digms. This study emphasizes the need to further investigate and refine molecular risk models to account for overlapping profiles.